The objectives of this proposal are to further preclinical development of unique two-photon-activated photodynamic therapy (TPPDT) triads that incorporate a nontoxic porphyrin photosensitizer, a tumor targeting group, and an imaging functionality, providing for noninvasive image-guided treatment of recurrent and refractory head and neck tumors deep below the skin surface that currently have low survival rates and few treatment options. SensoPath Technologies will develop a detailed understanding of the dosimetry of the process, involving the interplay of targeting the receptor on the tumor surface, the delivery of pulsed near infrared (NIR) laser light in the range 800-840 nm, the method of drug delivery with optimized concentration, and the role of oxygen level in the tumors blood supply. Image-guided TPPDT, in which the irradiation of the tumor is controlled by its digitized image throughout the 3D volume of the tumor, will define and incorporate optical tumor margins to ensure that the entire tumor is treated. Planned image-defined tumor treatment in tissue phantoms and xenograft SCID mouse models will provide the information necessary to effectively treat deep spontaneous head and neck tumors in companion canines as an out-patient low-cost model for human clinical treatment with rapid recovery, little scarring and no post-PDT light sensitivity.